Cell survival signal transduction

One of the important molecular mechanisms of cancer progression involves regulation of “programmed cell death” pathways, biochemical processes that are important in development and tissue homeostasis in multicellular organisms. In cancer, these “apoptotic” and cell survival pathways are disrupted or co-opted by genetic and epigenetic changes in the cancer cell genome and by oncogenic biochemical mechanisms that drive disease progression. We and others are interested in uncovering these cell survival and cell death regulatory processes in the belief that new targets for cancer therapy will emerge. One of our most recent areas of focus is testing the hypothesis that cholesterol, a lipid associated with cardiovascular disease, may play a role in cancer by altering cell survival signal transduction events. We have recently obtained evidence that cell survival signaling in prostate cancer is mediated by cholesterol-rich membrane domains called lipid rafts or detergent-resistant membranes (DRMs).

Selected Publications

Lin, J., Adam, R.M., Santiestevan, E., and Freeman, M.R. (1999) The phosphatidylinositol 3’ kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Research 59:2891-2897.

Lin, J., Hutchinson, L., Gaston, S.M., Raab, G., and Freeman, M.R. (2001) BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: A unique role for proHB-EGF in cell survival regulation. Journal of Biological Chemistry 276:30127-30132.

Kim, J., Adam, R.M., and Freeman, M.R. (2002) Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Research 62:1549-1554.

Zhuang, L., Lin, J., Lu, M.L., Solomon, K.R., and Freeman, M.R. (2002) Cholesterol-rich lipid rafts mediate Akt-regulated survival in prostate cancer cells. Cancer Research 62:2227-2231.

Adam, R.M., Kim, J., Lin, J., Orsola, A., Rice, D.C., and Freeman, M.R. (2002) Heparin-binding EGF-like growth factor stimulates androgen-independent prostate tumor growth and antagonizes androgen receptor function. Endocrinology 143:4599-4608.

Adam, R.M., Danciu, T., McClellan, D.L., Borer, J.G., Lin, J., Zurakowski, D., Weinstein, M.H., Rajjayabun, P., Mellon, J.K., and Freeman, M.R. (2003) A nuclear form of the heparin-binding EGF-like growth factor precursor is a feature of aggressive transitional cell carcinoma. Cancer Research 63:484-490.

Kim, J., and Freeman, M.R. (2003) JNK/SAPK mediates doxorubicin-induced differentiation and apoptosis in MCF-7 breast cancer cells. Breast Cancer Research and Treatment 79:321-328.

Zhuang, L., Kim, J., Adam, R.M., Solomon, K.R., and Freeman, M.R. (2005) Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. Journal of Clinical Investigation 115:959-968.

Kim, J., Adam, R.M., and Freeman, M.R. (2005) Trafficking of nuclear HB-EGF into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Research 65:8242-8249.

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